Prognostic markers of survival after combined mitotane- and platinum-based chemotherapy in metastatic adrenocortical carcinoma characterized for plasma mitotane level and ERCC1 protein expression analyses
Pasqualino Malandrino1, Abir Al Ghuzlan2, Marine Castaing3, Jacques Young4, Bernard Caillou2, Jean-Paul Travagli5, Dominique Elias5, Thierry de Baere6, Clarisse Dromain6, Philippe Chanson4, Martin Schlumberger1, Sophie Leboulleux1 & Eric Baudin1
Introduction: Mitotane and platinum-based chemotherapy are the main therapeutic choices for treating inoperable and/or metastatic adrenocortical carcinoma (ACC).
Objective: To search for prognostic parameters of survival in patients with metastatic ACC treated with combined mitotane- and platinum-based chemotherapy.
Patients: One hundred and thirty one consecutive patients with metastatic ACC treated at the Gustave-Roussy Institute (from 1993 to 2007) were retrospectively reviewed. Fifty-five patients with clinical, pathological and morphological data available together with detailed follow-up were enrolled.
Methods: Overall survival (OS) was evaluated from the start of platinum-based chemotherapy and response rate (RR) according to the RECIST criteria. Univariate and then multivariate analysis were used to check parameters impacting on OS. The landmark method was applied to analyze OS according to response to chemotherapy. Plasma mitotane levels at chemotherapy start (39 patients) and ERCC1 protein staining, evaluated by immunohistochemic as function of both percentage and intensity of cellular staining (33 patients), were analyzed.
Results: Independent predictors of survival were: surgery of primary tumor (yes vs no: median OS=13.5 versus 7.7 months; P=0.03); number of metastatic organs (≤2 vs >2: median OS=15.6 versus 7.1 months; P=0.03); response to chemotherapy (yes vs no: median OS=40.6 versus 9.6 months; P=0.001). Interestingly in case of plasma mitotane ≥14 mg/l median OS was 19.6 in respect to 9.5 months when <14 mg/l (P=0.07). Median OS wasnt different between ERCC1-low and ERCC1-high patients (13.3 versus 10.1 months), but considering only intensity staining, median OS was 14.5 and 7.6 months in patients with low and high ERCC1 intensity, respectively (P=0.42). Only the number of metastatic organs influenced RR (P=0.04).
Conclusion: Surgery of primary tumor, number of metastatic organs and response to chemotherapy are independent prognostic factors of survival after platinum-based therapy. Plasma mitotane ≥14 mg/l leads to a better survival. ERCC1 expression warrants further investigation in prospective studies.